HPIA 7 year old girl is brought by his mother because she is concerned that she is “not keeping up with the other children.” The pt is in first grade and is struggling to keep up with peers in reading. Both mom and the teacher have noticed she has difficulty sitting still and often blurts out responses in class. Mom also notes she has “more birthmarks that she used too.” Per mom she has always had a lot of freckles under her arms, but now she has more dark skin patches. The patient also complains of intermittent L leg and L arm numbness (described as “tingles”) and weakness.List items in the hx that would you help you solve the case:1. PMH/SH:2. Birth Hx:3. Social Hx:4. Family Hx:

Further History• Past Med/Surg Hx: Dx with scoliosis at school this year. No

infantile spasms. Fell and broke humorus 8 mo ago. – Meds: none– Allergies: none– Immunizations: Up to date

• Gynhx: No signs of early puberty or vaginal bleeding• Birth Hx: Normal vaginal delivery at term• Family Hx: Dad has HTN and lots of “skin tags” and has to

see lots of doctors.• Social Hx: Lives at home with mom and dad. No sick

contacts.Please list at least 3 items on your differential diagnosis1.2.3.

DDx• Neurofibromatosis – Type I– Type II

• Tuberous Sclerosis• ADHD• Learning Disability• Tenia Versicolor• McCune-Albright Syndrome• Radiculopathy/Vertebral stenosisBeside each diagnosis list items you will look for on physical exam that would

support or refute each one.

Physical Exam• Vitals: T: 98.6° F, P: 75 bpm, BP: 120/75, RR: 12,

SpO2: 99% on RA• Gen: Energetic throughout exam.• Skin: 7 brownish, smooth border, macules, the

smallest measuring 7mm. There is obvious freckling in both axilla as well as the inguinal region bilaterally. There is one small area of lighter skin that is new per mom.• HEENT: Head is without deformity. There are no

rashes of the face. There are multiple hyperpigmented nodules on the patients iris (see pic)• CV: wnl• Resp: wnl• Abd: wnl•M/S: mild scoliosis. No other boney abnl.• Neuro: AxOx3. CN’s II-XII intact. 4/5 strength in L

leg and arm, 2+ reflexes throughout. Slightly decreased sensation in the L arm. Cerebellar function intact.

What tests/evaluations (not imaging) would you order. (you may add more or use less than the numbers listed)

1.2.3.4.5.6.

Pt’s Father

Pt’s Eye Exam

Tests• CBC, CMP: wnl• Wood’s Lamp Exam of Hypopigmented spot:

– Negative fluorescence. • Genetic Testing: + for NF1 (neurofibromin) mutation• Testing of Visual Acuity: normal• Hearing Screen: Normal• Vanderbilt Assessment Tool for ADHD: positive• GH: normal

Order any imaging1.2.3.4.

Imaging1. CXR: Quick test to see

any major issues with thoracic bones

2. MRI thoracic spine for extremity symptoms

3. US Kidneys and Heart to check for angiomyolipomas and rhabdomyoma respecitively.*Done if you can’t rule out Tuberous Sclerosis

Classic dumbbell shaped paraspinal neurofibroma with displacement of spinal cord likely causing the patients extremity

symptoms.

Extra Imaging

Bilateral Optic Gliomas

Black arrows at top depicting neurofibromas on CXR

Consider your DDx and write your diagnosis

_____________________

Diagnosis: NF Type IConsider you DDx:

DDx Positive Negative

ADHD Hyperactivity at school, impulsivity. +Comments from teachers, + Vanderbilt screen, common with NF

Alone, it doesn’t explain the physical findings

Tuberous Sclerosis Ash leaf lesion, mental delay, No adenoma sebaceum (reddish brown papules on nose, cheeks. Negative woods lamp on ash leaf. No infantile seizures

Learning Disability Falling behind peers. Seems Physical findings of extremities, cutaneous findings. May be comorbidity but doesn’t explain all the findings

Tenia Versicolor Hypopigmented spot Negative woods lamp. Doesn’t explain extremity symptoms of developmental delay. Usually multiple locations and don’t tan in the sun.

McCune Albright Multiple hyperpigmented macules, hx bone fracture

Gigantism, facial bone abnormalities, café-au-lait spots are usually more irregular and located on back, normal Growth hormone

Vertebral Stenosis Numbness and tingling in extremities Multiple extremities involved, age

Therapy/Surveillance• Check-ups

– Evaluation for new neurofibromas and progression of lesions

– Annual BP measurement and formal ophthalmologic evaluation

– Neurodevelopmental assessment– Evaluation for skeletal changes (ie,

scoliosis, vertebral angulation, and limb abnormalities)

– Genetic Counseling

• Associated Tumors–Wilms– Pheochromocytoma– Juvenile CML

• Red Flags– Pain of unknown etiology–Weakness, numbness, tingling in

the extremities– Change in balance or coordination– Change in vision– Change in intensity or frequency of

headaches– Neurofibromas that change rapidly

in size and/or color, or cause pain– Abnormal neurologic examination– Sudden onset of hypertension– Regression of cognitive skills or

loss of developmental milestones– Significant deviation from

established pattern of growth

Summary• Multiple types of mutations (e.g. point, translocation,

deletion, etc) in the NF1 gene which turns off a tumor growth factor– 50% of cases are inherited (AD) and 50% are de novo mutations.

• ADHD is not uncommon with NF, so screening in suspected children is warranted.

• Order of appearance: Café au lait spots, axillary freckling, Lisch nodules, and neurofibromas

• Lab tests and Imaging are driven by the clinical picture. – Ex. Urine metanephrines for pheochromocytoma if persistent HTN

exists– Ex. MRI Orbits if you suspect optic gliomas or visual changes are

present

Overview of NF Type I• NIH Criteria– 6 or more café au lait

macules >5mm (prepubertal), >15 mm postpubertal.

– 2 or more NF’s or 1 plexiform type

– Freckling– Optic glioma– 2 or more lisch nodules– Bony lesion– 1st degree relative with NFI

NFI vs NFII

References:http://www.jaapa.com/neurofibromatosis-type-1-von-recklinghausen-disease/article/197450/http://www.uptodate.com/contents/neurofibromatosis-type-1-von-recklinghausens-disease?source=search_result&search=neurofibromatosis+children&selectedTitle=1~131#H6

NFI NFII

Chromosome/Protein 17 (neurofibromin) 22 (merlin)

Lisch Nodules + -

Café au lait spots + +

Freckling +++ +

Cognitive Delay + -

Cutaneous lesions + +

Bilateral Acoustic Neuromas - +

Malignant Transformation + -

Pigmented Plexiform NF’s + -

Dumbbell tumors (spinal) Neurofibromas schwannomas